ofirnoflast (HT-6184) / Halia Therap - LARVOL DELTA

OFIRNOFLAST, A FIRST-IN-CLASS NEK7 INHIBITOR, INDUCES ROBUST TRANSFUSION INDEPENDENCE AND MULTILINEAGE HEMATOLOGICAL IMPROVEMENT IN LOWER-RISK MYELODYSPLASTIC SYNDROME(LR-MDS): PHASE 2 RESULTS (EHA 2026) - "Ofirnoflast (HT-6184) is the first-in-class, oral, allosteric inhibitor of NEK7, a scaffold protein essential for NLRP3 inflammasome assembly...It also had an exceptional safety profile with no treatment-related serious adverse events. These results represent the first clinical validation that NEK7 blockade can durably suppress the NLRP3 inflammasome and restore hematopoiesis across all MDS subtypes, supporting Ofirnoflast as a transformative treatment for this high-unmet-need population."

P2 data • Cardiovascular • Hematological Disorders • Hematological Malignancies • Hypertension • Leukopenia • Myelodysplastic Syndrome • GATA1 • NLRP3 • SF3B1 • TNFA

Clinical Efficacy of the Novel Oral NEK7 Inflammasome Inhibitor Ofirnoflast in Erythropoietin-Refractory Lower-Risk Myelodysplastic Syndromes With High-Risk Mutational Profiles: A Case Series (SOHO 2026) - "Ofirnoflast demonstrated potent, multilineage hematologic improvement in ESA-refractory lower-risk MDS. Notably, CRs and clinical benefits were observed across diverse, high-risk molecular profiles (TP53, SF3B1, JAK2). Across the study, 55% of patients (10 of 18) achieved RBC-TI ≥8 weeks and 70% of responders (7 of 10) maintained TI ≥16 weeks (median duration, 28 weeks)."

Clinical • First-in-human • Tumor mutational burden • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • IDH2 • JAK2 • NLRP3 • PHF6 • SF3B1 • TET2 • TMB • TP53

Multilineage Hematologic Improvement in Lower-Risk Myelodysplastic Syndromes: Clinical Significance of Platelet and Neutrophil Recovery With Ofirnoflast, a Potent Allosteric Inhibitor of NEK7/NLRP3 Assembly (SOHO 2026) - "Ofirnoflast demonstrated meaningful multilineage hematologic activity in LR-MDS, with confirmed HI-N and HI-P in eligible patients, and durable responses lasting more than 200 days. The co-occurrence of erythroid improvement among HI-N and HI-P responders suggests a broad effect on hematopoietic progenitors across lineages. These findings support ofirnoflast as a potential multilineage-active agent in LR-MDS and warrant further evaluation in larger studies."

Clinical • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • NLRP3

Allosteric NEK7 Inhibition With Ofirnoflast (HT-6184) Suppresses Mitochondrial Stress, Reduces Systemic Inflammatory Cytokines, and Attenuates Clonal Expansion in Lower-Risk Myelodysplastic Syndrome (SOHO 2026) - "Ofirnoflast produced significant suppression of NLRP3-associated inflammatory and mitochondrial stress biomarkers, with evidence of clonal attenuation in a subset of LR-MDS patients. These data provide the first in-human validation of allosteric NEK7 inhibition as a potential disease-modifying strategy in MDS and establish pharmacodynamic biomarker correlates of clinical response, supporting further clinical development of ofirnoflast. ASC: apoptosis-associated speck-like protein containing a CARD, IL: interleukin, NEK7: NIMA-related kinase 7, NLRP3: NLR family pyrin domain containing 3, ox-mtDNA: oxidized mitochondrial DNA, S100A9: S100 calcium binding protein A9, TET2: tet methylcytosine dioxygenase 2, TLR: toll-like receptor, TNF-α: tumor necrosis factor alpha, TP53: tumor protein p53, VAF: variant allele frequency, ZRSR2: zinc finger CCCH-type RNA binding motif and serine/arginine rich 2."

First-in-human • IO biomarker • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CXCL8 • IL1B • IL6 • NLRP3 • S100A9 • TET2 • TNFA • TP53 • ZRSR2

Ofirnoflast (HT-6184), a First-in-Class Allosteric NEK7 Inhibitor, Achieves Durable Transfusion Independence and Hematologic Improvement–Erythroid in ESA-Refractory Lower-Risk Myelodysplastic Syndrome: Phase 2 Final Results (SOHO 2026) - "Ofirnoflast demonstrated a favorable safety profile and clinically significant efficacy in patients with ESA-refractory LRMDS, achieving TI in 55% of TD patients and 63% HI-E response, with a maximum median hemoglobin increase of 4.6 g/dL. These phase 2 results establish allosteric NEK7/NLRP3 inhibition as a potential mechanistically novel and effective treatment strategy in LRMDS. GATA-1: GATA binding protein 1, IL: interleukin, IPSS-R: Revised International Prognostic Scoring System, IWG: International Working Group, NEK7: NIMA-related kinase 7, NLRP3: NLR family pyrin domain containing 3, RBC: red blood cell, SF3B1: splicing factor 3b subunit 1, WHO: World Health Organization."

Clinical • P2 data • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • GATA1 • IL1B • NLRP3 • SF3B1

Ofirnoflast (HT-6184), a First-in-Class Allosteric NEK7 Inhibitor, Achieves Durable Transfusion Independence (TI) and Hematological Improvement-Erythroid (HI-E) in ESA-Refractory Lower-Risk Myelodysplastic Syndrome (LR-MDS): Phase 2 Final Results (SOHO 2026) - "Ofirnoflast demonstrated a favorable safety profile and clinically significant efficacy in patients with ESA-refractory LRMDS, achieving TI in 55% of TD patients and 63% HI-E response, with a maximum median hemoglobin increase of 4.6 g/dL. These phase 2 results establish allosteric NEK7/NLRP3 inhibition as a potential mechanistically novel and effective treatment strategy in LRMDS. GATA-1: GATA binding protein 1, IL: interleukin, IPSS-R: Revised International Prognostic Scoring System, IWG: International Working Group, NEK7: NIMA-related kinase 7, NLRP3: NLR family pyrin domain containing 3, RBC: red blood cell, SF3B1: splicing factor 3b subunit 1, WHO: World Health Organization."

Clinical • P2 data • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • GATA1 • IL1B • NLRP3 • SF3B1

Evaluate Ofirnoflast in Adults With Very Low- to Intermediate-risk Myelodysplastic Syndromes Requiring Transfusions (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Halia Therapeutics, Inc.

New P2 trial • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Halia Therapeutics Receives FDA Fast Track Designation for Ofirnoflast (HT-6184) in Lower-Risk Myelodysplastic Syndromes (PRNewswire) - "The designation follows encouraging Phase 2 results demonstrating durable transfusion independence and multilineage hematologic improvement and provides an important opportunity to work closely with the FDA as we advance ofirnoflast toward pivotal development."

Fast track • Myelodysplastic Syndrome

Halia Therapeutics to Present Final Phase 2 Ofirnoflast Data in Lower-Risk MDS at EHA2026 (PRNewswire) - "Highlights from the accepted abstract include: 67% overall HI rate among 30 evaluable patients, with multilineage activity: 62% HI-E, 60% HI-P, and 50% HI-N, 55% RBC transfusion independence for ≥8 weeks among transfusion-dependent patients (10/18), with 39% sustained for ≥16 weeks, Median duration of transfusion independence of 28.5 weeks...Additional efficacy, safety, biomarker, and quality-of-life data will be presented at the EHA2026 Congress."

P2 data • Myelodysplastic Syndrome

A Ph2 Study to Evaluate the Safety, Efficacy and Tolerability of HT-6184 and Semaglutide in Obese Participants With T2DM (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Halia Therapeutics, Inc. | N=50 ➔ 0 | Trial completion date: Aug 2026 ➔ Jan 2026 | Recruiting ➔ Withdrawn | Trial primary completion date: Aug 2026 ➔ Jan 2026

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Ph2 Study to Evaluate the Safety, Efficacy and Tolerability of HT-6184 and Semaglutide in Obese Participants With T2DM (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Halia Therapeutics, Inc. | Not yet recruiting ➔ Recruiting | Initiation date: Sep 2025 ➔ Jan 2026

Enrollment open • Trial initiation date • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

HT-6184-MDS-001: A Phase 2a Study of HT-6184 in Subjects With IPSS-R Very Low, Low or Intermediate Risk MDS and Anemia (clinicaltrials.gov) - P2 | N=37 | Active, not recruiting | Sponsor: Halia Therapeutics, Inc. | Trial primary completion date: Oct 2025 ➔ Mar 2026

Trial primary completion date • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

TP53 exon 7 (c.742C>T; p. Arg248Trp) vaf suppression by novel oral allosteric NEK7 inhibitor in a patient with low-risk myelodysplastic syndrome in A phase 2 clinical trial (ASH 2025) - P2 | "Ofirnoflast (HT-6184) is an oral, first-in-class allosteric inhibitor of NEK7 currently under evaluation in a Phase 2 trial in patients with low-risk MDS and symptomatic anemia (NCT07052006)...These findings suggest that ofirnoflast may restore endogenous anti-clonal immunity through inhibition of inflammasome signaling. Further evaluation in larger TP53-mutant MDS cohorts is warranted to confirm these preliminary observations and assess the potential of ofirnoflast as a targeted, immune-modulating therapy."

Clinical • P2 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • NLRP3 • TP53

The novel allosteric NEK7 inhibitor ofirnoflast (HT-6184) demonstrates robust and sustained hematologic response in subjects with IPSS-R very low, low or intermediate risk myelodysplastic syndrome (MDS) and symptomatic anemia (ASH 2025) - P2 | "Importantly, ofirnoflast supported sustained 32-week HI-E in difficult-to-treat ESA-refractory and ESA-intolerant populations. With a robust HI-E rate, favorable safety profile, absence of myelosuppression, arelevant and targeted mechanism of action, ofirnoflast offers a novel oral alternative that eases theburden of current treatments in a diverse MDS population."

Clinical • Anemia • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • CASP1 • GATA1 • IL1B • NLRP3 • SF3B1

Ofirnoflast suppresses heme-induced inflammation, representing a novel therapeutic strategy for hemolytic anemias (ASH 2025) - "Inhibition of the NLRP3inflammasome has been shown to mitigate inflammation and cell death in preclinical models ofhemolytic anemia.Ofirnoflast (HT-6184) is a novel, orally bioavailable small molecule that selectively inhibits NLRP3inflammasome activation by allosteric modulation of Nek7, a critical scaffolding protein forinflammasome assembly...Ofirnoflast potently inhibits heme-induced activation of the NLRP3 inflammasome in vitro,reducing both inflammatory cytokine release and pyroptotic markers. These findings supportcontinued investigation of Ofirnoflast as a promising therapeutic approach in sickle cell diseaseand other hemolytic anemias characterized by NLRP3-mediated inflammation."

Anemia • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease • CASP1 • IL1B • NLRP3

The novel allosteric NEK7 inhibit ofirnoflast (HT-6184) reduces oxidized mitochondrial DNA in patients with low-risk myelodysplastic syndrome (ASH 2025) - P2 | "Notably, some patients with substantial reductions in ox‑mtDNA did not meethematologic response criteria, suggesting that absolute ox‑mtDNA levels may be more clinically relevantthan percent change alone. These findings support further evaluation of alternative dosing, schedules,and treatment durations to determine whether achieving lower circulating ox‑mtDNA concentrationsmay enhance the likelihood of hematologic response in patients with low-risk MDS."

Clinical • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • NLRP3

The novel allosteric NEK7 inhibitor ofirnoflast (HT-6184) suppresses IL-8 and other pro-inflammatory cytokines in patients with low-risk myelodysplastic syndrome and symptomatic anemia (ASH 2025) - P2 | "These findings support further evaluation of inflammasome modulation as apotential strategy to improve hematopoiesis in LR‑MDS. Additionally, Larger studies with expandedsampling will clarify the therapeutic relevance of cytokine reduction in LR-MDS."

Clinical • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CXCL8 • IL18 • IL1B • IL6 • NLRP3 • TNFA

Targeting NLRP3 with ofirnoflast, alone or in combination with semaglutide, ameliorates inflammatory anemia associated with obesity-induced inflammation in rodent models (ASH 2025) - "Ofirnoflast (HT-6184) is aselective, orally available NLRP3 inflammasome inhibitor that targets the Nek7 scaffold protein.This study evaluated the therapeutic potential of Ofirnoflast, alone or in combination with theGLP-1 receptor agonist semaglutide, in restoring hematologic function in diet-induced obesemice.Objective:To determine whether pharmacologic inhibition of the NLRP3 inflammasome with Ofirnoflast,alone or in combination with the GLP-1 agonist semaglutide, can prevent or reverse obesity-associated inflammatory anemia in a preclinical diet-induced obese mouse model.Male C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks to induce obesity and randomizedinto four groups: HFD control, semaglutide (0.03 mg/kg), Ofirnoflast (5 mg/kg), and Ofirnoflast +semaglutide...Obesity-associated anemia of inflammation is driven in part by NLRP3-mediated inflammatorysignaling. Pharmacologic inhibition of the NLRP3 inflammasome with Ofirnoflast reduced adiposeinflammation..."

Combination therapy • Preclinical • Anemia • Genetic Disorders • Hematological Disorders • Inflammation • Obesity • NLRP3

Ofirnoflast, a novel inflammasome inhibitor, rewires transcriptional programs and shows clinical and preclinical efficacy in myeloid neoplasms (ASH 2025) - P1 | "Furthermore, genetic ablationof IL1R1 in Tet2-mutant cells or pharmacologic inhibition of IL1R1 in primary MDS/CMML patient-derivedcells with Anakinra abrogated the anti-leukemic effects of ofirnoflast, indicating that its therapeuticactivity is primarily mediated through suppression of chronic inflammation driven by the IL-1β/IL1R1 axis.In vivo, ofirnoflast treatment reduced leukemic burden by ~3-fold in both MDS/AML (n = 5, P = 0.005) andCMML (n = 7–9, P = 0.04) patient-derived xenograft models. scRNA-seq of treated xenografts revealed adual mechanism of action: (1) suppression of inflammatory and proliferative signaling pathways (NF-κB,TNF, and cell cycle genes), and (2) induction of apoptosis and erythroid differentiation programs,corroborating both molecular and functional in vivo and in vitro findings.Translating these insights to the clinic, a Phase 1 trial (n = 64; NCT05447546) in healthy volunteersshowed that ofirnoflast significantly reduced serum levels..."

Preclinical • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CASP8 • CD34 • GATA1 • IL18 • IL1B • IL1R1 • IL6 • NLRP3 • PYCARD • TET2

Halia Therapeutics Announces Positive Phase 2a Data for Ofirnoflast in Lower-Risk MDS at ASH 2025 (PRNewswire) - "72% of patients (13/18) achieved HI-E at Week 16, with responders showing a median hemoglobin increase of 3.5 g/dL. Strong activity in difficult-to-treat patients, including 91% HI-E in ESA-refractory and 75% HI-E in ESA-intolerant subjects. Consistent responses across disease biology, with HI-E observed across transfusion burden categories, WHO morphologic subtypes, and major mutation groups (SF3B1, TET2, DNMT3A, ASXL1, TP53)....Halia is finalizing the dataset and preparing to initiate a global Phase 3 pivotal trial in early 2026."

New P3 trial • P2a data • Myelodysplastic Syndrome

Ex-Vivo Human Whole Blood Assay for Evaluating the Pharmacodynamics of HT-6184: Reduction in NLRP3 Inflammasome Mediated Cytokine Production (ASH 2023) - "In addition, this assay has the potential to be used to measure the pharmacodynamic properties and the efficacy of HT-6184 and other inflammasome inhibitors in future healthy volunteer clinical trials. In conclusion, this study highlights the importance of innovative and physiologically relevant assay systems in identifying and evaluating potential therapeutic agents for inflammatory diseases."

PK/PD data • Preclinical • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • IL18 • IL1B • IL6 • NLRP3 • TNFA

HT-6184 Inhibits the Formation of the NLRP3 Inflammasome in Human Monocytic THP-1 Cells (ASH 2023) - "Since THP-1 cells are a monocytic cell line, this data suggests our ability to inhibit the NLRP3 pathway in hematological disorders effectively. By preventing inflammasome formation and activation, we expect to be able to reduce disease burden in hematological diseases."

Hematological Disorders • GLI2 • IL18 • IL1B • NLRP3

Modulation of NLRP3 Inflammasome in Monocytes By HT-6184 in a Single-Cell Proteomic Study (ASH 2023) - "Further research should explore the characteristics of HT-6184 and its ability to modulate the inflammasome in diverse in vitro and in vivo models. The modulation of the NLRP3 inflammasome by HT-6184 holds potential therapeutic implications for managing inflammatory disorders associated with dysregulated NLRP3 activation."

CNS Disorders • Immunology • Infectious Disease • Inflammation • Metabolic Disorders • CXCL8 • IL18 • IL1B • NLRP3 • TNFA

Halia Therapeutics to Present Groundbreaking Data on Novel Allosteric NEK7 Inhibitor Ofirnoflast at the 2025 American Society of Hematology Annual Meeting (PRNewswire) - "The presentations will feature comprehensive clinical...data on orfinoflast (HT-6184), a novel allosteric NEK7 inhibitor targeting the NLRP3 inflammasome, demonstrating its potential across multiple hematologic conditions, including myelodysplastic syndrome, hemolytic anemias, and inflammatory conditions. Clinical data from the ongoing study of orfinoflast demonstrate robust and sustained hematologic responses in patients with IPSS-R very low, low, or intermediate risk myelodysplastic syndrome (MDS) and symptomatic anemia."

Clinical data • Anemia • Myelodysplastic Syndrome

Preclinical studies presented at ASH showcase ofirnoflast's broader therapeutic potential, including its ability to suppress heme-induced inflammation, representing a novel therapeutic strategy for hemolytic anemias (PRNewswire) - "Additional research demonstrates that targeting NLRP3 with ofirnoflast, alone or in combination with semaglutide, ameliorates inflammatory anemia associated with obesity-induced inflammation in rodent models."

Preclinical • Anemia • Obesity